Descriptions

Histone deacetylase (HDAC) inhibitors are undergoing clinical trials as anticancer agents, but some exhibit resistance mechanisms
linked to anti-apoptotic Bcl-2 functions, such as BH3-only protein silencing. HDAC inhibitors that reactivate BH3-only family
members might offer an improved therapeutic approach. We show here that a novel seleno-α-keto acid triggers global histone
acetylation in human colon cancer cells and activates apoptosis in a p21-independent manner. Profiling of multiple survival factors
identified a critical role for the BH3-only member Bcl-2-modifying factor (Bmf). On the corresponding BMF gene promoter, loss of
HDAC8 was associated with signal transducer and activator of transcription 3 (STAT3)/specificity protein 3 (Sp3) transcription
factor exchange and recruitment of p300. Treatment with a p300 inhibitor or transient overexpression of exogenous HDAC8
interfered with BMF induction, whereas RNAi-mediated silencing of STAT3 activated the target gene. This is the first report to
identify a direct target gene of HDAC8 repression, namely, BMF. Interestingly, the repressive role of HDAC8 could be uncoupled
from HDAC1 to trigger Bmf-mediated apoptosis. These findings have implications for the development of HDAC8-selective
inhibitors as therapeutic agents, beyond the reported involvement of HDAC8 in childhood malignancy.